• Test Code:
    1145
  • Department:
  • Test Synonyms:
    C19orf12NBIA
  • CPT Code(s):
    81479
Background:

Mitochondrial-membrane Protein-Associated Neurodegeneration (MPAN) is characterized by progressive dystonia, spasticity, paraparesis or tetraparesis, optic atrophy, psychiatric changes (ADHD-like behavior, mood swings), and evidence of iron accumulation in both the globus pallidus and substantia nigra on T2-weighted MRI.  Onset generally occurs in childhood to early adulthood with slow progression and survival well into adulthood. 

MPAN is observed in ~10% of NBIA patients and mutations in c19orf12 are observed in 95% of patients with a clinical diagnosis of MPAN. Mutations in MMIN are observed in ~40% of patients with a negative mutation test for other NBIA-associated genes, eg. PANK2, PLA2G6, CP and FTL (Hartig et al. 2011).

Reasons for Referral:

  • Confirmation of a suspected diagnosis in patients with the hallmark findings of MPAN.
  • Further assessment of patients with clinical diagnosis of idiopathic Neurodegeneration with Brain Iron Accumulation (NBIA) who do not have an eye-of-the-tiger sign and/or have had mutations ruled out in PANK2 or PLA2G6.
  • Carrier testing of family members of MPAN patients with known mutations.

Methodology:

Sequencing using either Sanger Sequencing or Next-Generation Sequencing.

Sanger Sequencing:  Sequencing of c19orf12 is carried out by amplification of all exons and intron/exon boundaries followed by bi-directional Sanger sequencing. The sensitivity of full gene sequencing is estimated to be approximately 99% for single nucleotide substitutions and small insertions/deletions.  All nucleotide changes are analyzed within the context of current databases and literature to predict pathogenicity.

NGS:  Next generation sequencing will analyze the exons or coding regions of c19orf12 using Illumina NextSeq 500 technology.  Samples are prepared using hybridization probes to enrich exonic regions.  Promoter, intronic, etc. regions are not assessed on our assay, but may contain variants that impact gene function.

Test reporting follows the ACMG Standards & Guidelines for Clinical Genetics Laboratories, Ultra-Rare Disorders Guidelines, and Interpretation of Sequence Variants Guidelines.

Specimen Requirements:

Blood: EDTA or ACD (Solution A or B):

  • Adult:  5mL
  • Child:  5mL
  • Infant:  2-3mL

 DNA: 10µg at a minimum of 100ng/µL

Prenatal:

  • Direct Amniotic Fluid (10-20mL)
  • Direct CVS
  • Cultured Amnio or CVS (2-T25 flasks)

     

 Notice Regarding Molecular Genetic Testing on CVS or Amniotic Fluid Specimens:

  • Maternal cell rule-out testing will be performed on all prenatal specimens received. Please provide maternal blood in addition to the fetal specimen. Additional charges apply for the maternal cell rule-out test.
  • All genetic testing performed on Direct CVS or Amniotic Fluid specimens will be confirmed on cell cultures prepared by Knight Diagnostic Laboratories. Cell cultures will be prepared from the specimen received. Additional charges apply for confirmatory testing.

Test Performed (Days):

Weekly

Turn Around Time:

14 – 21 days

Shipment Sensitivity Requirements:

  • Keep specimen cold during transit, but do not ship on dry ice. 
  • Please contact Client Services at (855) 535-1522 for shipping kits and instructions. 
  • Use the cold pack provided in the KDL shipping kit. 
  • Ship the specimen via overnight express, using the FedEx priority overnight label provided.

References:

  1. Hartig MB, Iuso A, Haack T, et al.  Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.  Am J Hum Genet. 2011 Oct 7;89(4):543-50.

Additional Info:

The Knight Cancer Institute at Oregon Health & Science University is a pioneer in the field of precision cancer medicine. The institute's director, Brian Druker, M.D., helped prove it was possible to shut down just the cells that enable cancer to grow. This breakthrough has made once-fatal forms of the disease manageable and transformed how cancer is treated. The OHSU Knight Cancer Institute is the only National Cancer Institute-designated Cancer Center between Sacramento and Seattle – an honor earned only by the nation's top cancer centers. It is headquarters for one of the National Cancer Institute's largest research collaboratives, SWOG, in addition to offering the latest treatments and technologies as well as hundreds of research studies and clinical trials.

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